Method for Monofluoromethylation of Organic Substrates to Prepare Biologically Active Organic Compounds

ABSTRACT

Described is a process for the preparation of monofluoromethylated organic biologically active compounds using monofluoromethylated reagents. Fluticasone Propionate and Fluticasone Furoate can be prepared using, for example, S-monofluoromethyl-S-phenyl- 2,3,4,5 -tetramethylphenylsulfonium tetrafluoroborate as monofluoromethylating reagent instead of bromofluoromethane.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention is a divisional application of U.S. Ser. No.13/701,207 filed Mar. 14, 2013, now allowed, which claims the benefit ofthe PCT/GB2011/000834 filed Jun. 1, 2011, which claims priority to Ser.No. PT/105139 filed Jun. 1, 2010.

BACKGROUND OF THE INVENTION

The carbon-fluorine bond is commonly found in pharmaceutical andagrochemical products, because it is generally metabolically stable andthe fluorine atom acts as a bioisostere of the hydrogen atom (Ann M.Thayer “Fabulous Fluorine” Chemical and Engineering News, Jun. 5, 2006,Volume 84, pp. 15-24). Nowadays around 20% of all pharmaceuticalcompounds and 30-40% of agrochemicals on the market contain fluorine.Fluorination and fluoroalkylation are the two major synthetic methods toprepare selectively fluorinated organic compounds. Themonofluoromethylation (selective introduction of a CH₂F group into theorganic molecule) is less studied than fluorination.

The exploration of di- and monofluoromethylated compounds as organicbiologically active compounds has emerged recently. As a result, avariety of structurally diverse CH₂F-containing drugs have beendeveloped, such as: Afloqualone, Fluticasone Propionate (Jinbo Hu; WeiZhang; Fei wang; Chem. Commum., 2009, 7465-7478), the anaestheticSevoflurane, Fluticasone Furoate.

The efficient and selective incorporation of monofluoromethylatedmoieties into the organic molecule is beneficial for the synthesis ofthe target molecule. The process is usually carried out directly usingCH₂FBr or indirectly, using CH₂BrI or CH₂ClI, among others. Thesecompounds are known as hydrochlorofluorocarbons or freons (HCFCs), whichis a subclass of chlorofluorocarbons (CFCs).

Every permutation of fluorine, chlorine, and hydrogen on the methane andethane core has been examined and most have been commercialized.Furthermore, many examples containing bromine are known for highernumbers of carbon as well as related compounds. The use of this class ofcompounds includes refrigerants, blowing agents, propellants inmedicinal applications, and degreasing solvents (M. Rossberg et al.“Chlorinated Hydrocarbons” in Ullmann's Encyclopedia of IndustrialChemistry 2006, Wiley-VCH, Weinheim).

Unfortunately, due to their high stability, CFCs do not decompose in thelower atmosphere as many industrial chemicals do. In fact they areaccumulating and eventually rise to the stratosphere. Ultravioletradiation in the stratosphere breaks the CFCs apart, and the releasedchlorine atoms destroy the ozone layer. For this reason, the manufactureof such compounds is being phased out according to the Montreal Protocol(Pool, R. 1989. The elusive replacements for CFCs. Science 242: 666).Under the Montreal Protocol, it was agreed to start reducing theirconsumption and production in 2015.

Recently, Prakash et al. reported a new electrophilicmonofluoromethylation reagent for direct transfer of +CH₂F(S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfoniumtetrafluoroborate) to certain nucleophiles such as sulfonic acids,tertiary amines, imidazole derivatives, and phosphine (G. K. SuryaPrakash; Istvan Ledneczki; Sujith Chacko; George A. (Olah; Org. Lett.,vol. 10, No. 4, 2008).

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Schematic illustration of synthesis of fluticasone propionateand fluticasone furoate.

FIG. 2. Schematic illustration showing monofluoromethylating reagents.

DETAILED DESCRIPTION OF THE INVENTION

We have now devised a way of introducing the —CH₂F group onto a sulphuratom, in particular a thiol (S—H) group, and in this way are able toavoid the use of reagents that deplete the ozone layer. Hence, forexample, S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfoniumtetrafluoroborate (a) or triflate can be used to prepare FluticasonePropionate and Fluticasone Furoate as shown in FIG. 1.

This method can also be used for the preparation of monofluoromethylatedintermediate compounds, such as quaternary amines, tetrafluoroboratesalts, monofluoromethylated imidazoles tetrafluoroborate salts andsulfonic salts and in turn each of these compounds can also be used toprepare Fluticasone Propionate and Fluticasone Furoate or other organicbiologically active compounds containing a CH₂F group, such asAfloqualone and Sevoflurane.

According to one aspect of the present invention, there is provided amethod of preparing an organic biologically active compound containing a“CH₂F” moiety, which method comprises the use of a monofluoromethylatingreagent characterized by one of the following formulas I, II and III:

wherein:

R₁, R₂, R₃ is independently selected from the group consisting ofhydrogen, alkyl or aryl; and

R₄ is an anion suitable to form a salt of the reagents presented above,selected from the group consisting of tetrafluoroborate, triflate andhalogen.

In a preferred aspect, the method of the invention is used to provide acompound of Formula IV, such as fluticasone furoate or fluticasonepropionate.

In another aspect the invention provides the use of amonofluoromethylating reagent in the preparation of an organicbiologically active compound containing a “CH₂F” moiety.

Suitably, the organic biologically active compound may be obtained bymonofluoromethylation of a suitable organic substrate, which istypically a precursor compound. The organic substrate may be animmediate or direct precursor compound to the organic biologicallyactive compound, or may be an earlier intermediate compound at anyappropriate stage in the synthetic process. The stage ofmonofluoromethylation in the synthetic process will generally bedetermined by the active compound in question, as will be clear to thoseskilled in the art.

By “organic biologically active compound” we mean an organic compoundwhich is of medical or therapeutic use in the broadest sense. Typically,the compounds are pharmaceutically active compounds. Preferred compoundsinclude steroidal compounds, particularly glucocorticoid compounds,especially glucocorticoids such as fluticasone.

Preferably, the organic substrate or precursor compound comprises athiol group (S—H). Preferred compounds include steroidal compounds,particularly those comprising a thiol group. Glucocorticoid compoundsare particularly preferred, especially precursors to pharmaceuticallyactive glucocorticoids such as fluticasone.

In addition, if desired, the organic substrate or precursor compound maycomprise one or more hydroxyl (—OH) groups. We have found that,surprisingly, compounds having one or more hydroxyl groups can besatisfactorily monofluoromethylated (especially at a thiol (S—H) group)without needing to protect the hydroxyl group (for example, at the C₁₁position in a steroidal compound).

Thus, in a preferred aspect, there is provided a method of preparing anorganic biologically active compound containing a “CH₂F” moiety, whichmethod comprises the step of monofluoromethylating an organic substrateor precursor compound for the said active compound, which substrate orprecursor comprises a thiol (S—H) group, using a monofluoromethylatingreagent characterised by one of the following formulas I, II and III:

wherein:

R₁, R₂, R₃ is independently selected from the group consisting ofhydrogen, alkyl or aryl; and

R₄ is an anion suitable to form a salt of the reagents presented above,selected from the group consisting of tetrafluoroborate, triflate andhalogen.

Organic biologically active compounds can be obtained bymonofluoromethylation of organic substrates with the followingmonofluoromethylating reagents:

In the compound of formula II, “alkyl” is preferably a primary alkylwith from one to five carbon atoms (C₁-C₅), with methyl particularlypreferred. However, branched alkyl may be used if desired, and mayoptionally be substituted. “Aryl” is preferably phenyl or substitutedphenyl.

In terms of the amounts of substrate and monofluoromethylating reagentused, preferably from 0.9 to 2 mole equivalents of monofluoromethylatingreagent is used per mole of organic substrate (or precursor compound). Aratio of from about 1:1 to 1:1.2 (substrate:reagent) is particularlysuitable, particularly when making fluticasone derivatives or similarsteroidal compounds.

The temperature at which the reaction between substrate andmonofluoromethylating reagent is carried out is suitably from −15° C. to50° C. For many reactions, room temperature (20-25° C.) is suitable

EXAMPLES

The following reagents are given as examples but do not limit the scopeof the invention:

S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfoniumtetrafluoroborate,S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium triflate,salts thereof

P-monofluoromethyltriphenylphosphonium tetrafluoroborate,P-monofluoromethyltriphenylphosphonium triflate and salts thereof

N-(monofluoromethyl) triethylammonium tetrafluoroborate,N-(monofluoromethyl) triethylammonium triflate and salts thereof

N-(monofluoromethyl)-N-phenyl-dimethylammonium tetrafluoroborate,N-(monofluoromethyl)-N-phenyl-dimethylammonium triflate and saltsthereof

EXAMPLE 1 Preparation of fluticasone 17-propionate withS-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium triflatein dichloromethane:

2 g (4.27 mmol) of 17-propionate carbothioic acid (full name:6α,9α-Difluoro-11β-hydroxy, 16α-methyl-3-oxo-17α-(propionyloxy)androsta-1,4-diene-17β-carbothioic acid) was dissolved in 49 ml ofdichloromethane. 0.756 g (0.54 eq) of cesium carbonate and 1.928 g (1.06eq) of S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfoniumtriflate were added. The resulting mixture was stirred at roomtemperature until the reaction is complete. The mixture was added to 250ml of heptane. The dichloromethane was removed by distillation. Thesolid was isolated by filtration, washed with heptane and dried undervacuum at a temperature below 35° C. The solid was recrystallized from amixture of acetone and water. The salts are purged during thisrecrystallization.

EXAMPLE 2 Preparation of fluticasone 17-propionate withS-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium triflatein acetonitrile:

5 g (10.7 mmol) of 17-propionate carbothioic acid was suspended in 50 mlof acetonitrile. 3.39 g (1 eq) of cesium carbonate was added. Theresulting suspension was stirred for 5 minutes at room temperature. 4.54g (1.0 eq) ofS-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium triflatewas added. The suspension was stirred at room temperature until thereaction is complete. The solid was isolated by filtration, washed with10 ml of acetonitrile and then with 10 ml of heptane at 5° C. The solidwas dried under vacuum at a temperature below 35° C. The solid wasrecrystallized from a mixture of acetone and water. The salts are purgedduring this recrystallization.

EXAMPLE 3 Preparation of fluticasone 17-propionate withS-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfoniumtetrafluoroborate in dichloromethane:

5 g (10.7 mmol) of 17-propionate carbothioic acid was dissolved in 50 mlof dichloromethane. 3.39 g (1 eq) of cesium carbonate was added and thesolution turned into a suspension. The suspension was stirred for 40minutes at room temperature. 4.57 g (1.18 eq) ofS-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenyl sulfoniumtetrafluoroborate was added. The mixture was stirred at room temperatureuntil the reaction is complete. The solid was isolated by filtration,washed with 10 ml of dichloromethane and washed twice with 10 ml ofheptane. The solid was dried under vacuum at a temperature below 35° C.The solid was recrystallized from a mixture of acetone and water. Thesalts are purged during this recrystallization.

EXAMPLE 4 Preparation of fluticasone 17-propionate withS-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfoniumtetrafluoroborate in acetonitrile:

5 g (10.7 mmol) of 17-propionate carbothioic acid was suspended in 50 mlof acetonitrile. 3.39 g (1 eq) of cesium carbonate was added. Theresulting suspension was stirred for 5 minutes at room temperature. 3.9g (1 eq) ofS-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfoniumtetrafluoroborate was added. The mixture was stirred at room until thereaction is complete. The solid was isolated by filtration, washed with10 ml of acetonitrile at 5° C. and dried under vacuum at a temperaturebelow 35° C. The solid was recrystallized from a mixture of acetone andwater. The salts are purged during this recrystallization.

EXAMPLE 5 Preparation of fluticasone 17-propionate withN-(monofluoromethyl) triethyl ammonium triflate in acetonitrile:

0.5 g (1.07 mmol) of 17-propionate carbothioic acid was suspended in 5ml of acetonitrile. 0.218 g (0.63 eq) of cesium carbonate and 0.604 g(2.13 eq) of N-(monofluoromethyl) triethylammonium tetrafluoroboratewere added. The mixture was stirred at room temperature until thereaction is complete. The solid was isolated by filtration, washed with0.5 ml of acetonitrile and then with 1 ml of water. The solid was driedunder vacuum at a temperature below 35° C.

EXAMPLE 6 Preparation of fluticasone 17-propionate withN-(monofluoromethyl)-N-phenyl-dimethylammonium triflate in acetonitrile:

0.5 g (1.07 mmol) of 17-propionate carbothioic acid was suspended in 5ml of acetonitrile. 0.218 g (0.63 eq) of cesium carbonate was added. Theresulting suspension was stirred for 30 minutes prior to the addition of0.5 g (1.5 eq) of N-(monofluoromethyl)-N-phenyl-dimethylammoniumtriflate. The resulting mixture was stirred at room temperature untilthe reaction is complete. The solid was isolated by filtration, washedwith 5 ml of cold acetonitrile and dried at a temperature below 35° C.The solid was suspended in water to remove the salts and then dried.

EXAMPLE 7 Preparation of fluticasone 17-propionate withP-monofluoromethyltriphenylphosphonium tetrafluoroborate inacetonitrile:

1 g (2.13 mmol) of 17-propionate carbothioic acid was suspended in 12 mlof acetonitrile. 0.45 g (0.65 eq) of cesium carbonate and 1.4 g (1.7 eq)of P-monofluoromethyltriphenylphosphonium tetrafluoroborate were added.The mixture was stirred at room temperature until the reaction iscomplete. The solid was isolated by filtration, washed twice with 3 mlof acetonitrile previously cooled to 5° C. and then with 3 ml of water.The solid was dried under vacuum at a temperature below 35° C.

EXAMPLE 8 Preparation of fluticasone 17-furoate withS-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium triflatein acetonitrile:

2.5 g (4.93 mmol) of carbothioic acid 17-furoate (full name:6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid) was suspended in 10 ml of acetonitrile. 1.04 g (0.65 eq) of cesiumcarbonate and 3.0 g (1.43 eq) ofS-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium triflatewere added. The resulting suspension was stirred at room temperatureuntil the reaction is complete. The solid was isolated by filtration,washed twice with 2.5 ml of acetonitrile previously cooled to 5° C. anddried under vacuum at a temperature below 35° C. The solid isrecrystallized from a mixture of acetone and water. The salts are purgedduring this recrystallization.

EXAMPLE 9 Preparation of fluticasone 17-furoate withS-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfoniumtetrafluoroborate in acetonitrile:

2.5 g (4.93 mmol) of carbothioic acid 17-furoate was suspended in 10 mlof acetonitrile. 1.04 g (0.65 eq) of cesium carbonate and 2.1 g (1.18eq) of S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfoniumtetrafluoroborate were added. The resulting suspension was stirred for 1hour at room temperature. The solid was isolated by filtration, washedtwice with 2.5 ml of acetonitrile previously cooled to 5° C. The solidwas dried under vacuum at a temperature below 35° C. The solid isrecrystallized from a mixture of acetone and water. The salts are purgedduring this recrystallization.

EXAMPLE 10 Preparation of fluticasone 17-furoate withN-(monofluoromethyl)-N-phenyl-dimethylammonium triflate in acetonitrile:

0.5 g (0.987 mmol) of carbothioic acid 17-furoate was suspended in 5 mlof acetonitrile. 0.208 g (0.65 eq) of cesium carbonate and 0.4 g (1.34eq) of N-(monofluoromethyl)-N-phenyl-dimethylammonium triflate wereadded. The resulting suspension was stirred for 4 hour at roomtemperature. The solid was isolated by filtration, washed twice with 1ml of acetonitrile previously cooled to 5° C. and then with 1 ml ofdeionised water. The solid was dried under vacuum at a temperature below35° C. The solid is recrystallized from a mixture of acetone and water.The salts are purged during this recrystallization.

It is evident to one skilled in the art that this invention is notlimited to the foregoing examples, and that can be embodied in otherspecific forms without departing from the scope of the invention. Thus,the examples should be considered as illustrative and not restrictive,reference being made to the claims, and that all changes which comewithin the meaning and range of equivalency of claims be embracedtherein.

What is claimed is:
 1. A method of preparing a pharmaceutically activecompound containing a “CH₂F” moiety on a sulphur atom, which methodcomprises the use of a monofluoromethylating reagent characterized byone of the following formulas II and III:

wherein: R₁, R₂, R₃ is independently selected from the group consistingof hydrogen, alkyl or aryl; and R₄ is an anion suitable to form a saltof the reagents presented above, selected from the group consisting oftetrafluoroborate, triflate and halogen.
 2. A method according to claim1, wherein the monofluoromethylating reagent is a compound with FormulaII:

wherein: R₁, R₂ and R₃ is independently selected from the groupconsisting of hydrogen, alkyl or aryl; and R₄ is selected from the groupconsisting of tetrafluoroborate, triflate and halogen.
 3. A methodaccording to claim 1, wherein the monofluoromethylating reagent is acompound with Formula III:

wherein: R₄ is selected from the group consisting of tetrafluoroborate,triflate and halogen.
 4. A method according to claim 2, wherein R₁, R₂and R₃ are ethyl groups and R₄ is tetrafluoroborate or triflate.
 5. Amethod according to claim 2, wherein R₁, R₂ are both methyl, R₃ is aryland R₄ is tetrafluoroborate or triflate.
 6. A method according to claim2, wherein R₁, R₂ are both methyl, R₃ is phenyl and R₄ istetrafluoroborate or triflate.
 7. A method according to claim 3, whereinR₄ is triflate or tetrafluoroborate.
 8. A method according to claim 1,wherein the pharmaceutically active is a compound of Formula IV:

wherein: R is selected from the group consisting of hydroxyl, furoateand propionate.
 9. A method according to claim 8, wherein R ispropionate or furoate.
 10. A method according to claim 8, wherein saidmonofluoromethylating reagent is reacted with6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid or 6α,9α-Difluoro-11β-hydroxy, 16α-methyl-3-oxo-17α-(propionyloxy)androsta-1,4-diene-17β-carbothioic acid to give the correspondingcompound of formula IV.
 11. A method according to claim 8, wherein thecompound of formula IV is prepared usingS-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfoniumtetrafluoroborate salt as monofluoromethylating reagent.
 12. A methodaccording to claim 8, wherein the compound of formula IV is preparedusing S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfoniumtriflate salt as monofluoromethylating reagent.
 13. A method accordingto claim 8, wherein the compound of formula IV is prepared usingN-(monofluoromethyl) triethyl ammonium triflate salt asmonofluoromethylating reagent.
 14. A method according to claim 8,wherein the compound of formula IV is prepared usingN-(monofluoromethyl)-N-phenyl-dimethylammonium triflate salt asmonofluoromethylating reagent.
 15. A method according to claim 8,wherein the compound of formula IV is prepared usingN-(monofluoromethyl)-N-phenyl-dimethylammonium tetrafluoroborate salt asmonofluoromethylating reagent.
 16. A method according to claim 8,wherein the compound of formula IV is prepared usingP-monofluoromethyltriphenylphosphonium tetrafluoroborate salt asmonofluoromethylating reagent.
 17. A method according to claim 1,wherein the preparation of the pharmaceutically active compoundcomprises an organic solvent.
 18. A method according to claim 17,wherein the solvent is selected from the group consisting ofacetonitrile, heptane, hexane, cyclohexane, methyl tert-butyl ether(MTBE), dimethylformamide (DMF), toluene, 1,2-dichloromethane,α,α,α-trifluorotoluene, tetrahydrofurane (THF), methyl-THF,1,2-dimethoxyethane and mixtures thereof.
 19. A method according toclaim 1, wherein the preparation of the pharmaceutically active compoundcomprises use of a base.
 20. A method according to claim 19, wherein thebase is a weak base.
 21. A method according to claim 19, wherein thebase is an inorganic carbonate.
 22. A method according to claim 21,wherein the base is selected from the group consisting of cesiumcarbonate, sodium carbonate and potassium carbonate, and mixturesthereof.
 23. A method according to claim 22, wherein the base is cesiumcarbonate.
 24. A pharmaceutically active compound, the compoundcomprising a monofluoromethylating reagent as defined in claim 1 andcontaining a “CH₂F” moiety on a sulphur atom.
 25. The compound accordingto claim 24, wherein the “CH₂F” moiety is introduced on to a thiol group(S—H) in the preparation of the pharmaceutically active compound. 26.The compound according to claim 24, wherein the said compound is acompound of Formula IV

wherein: R is selected from the group consisting of hydroxyl, furoateand propionate.
 27. The compound according to claim 26, wherein theorganic substrate which is monofluoromethylated comprises a hydroxylgroup in its structure.